Pharmacological Treatment of Tachyarrhythmias in Acute Myocardial Infarction - a Review

The most common etiology of AF in the setting of AMI appears to be atrial stretching due to heart failure with elevation in left atrial pressures¹⁰. In patients with AMI complicated with severely depressed left ventricle systolic function, AF is precipitated or exacerbated by on-going atrial ischemia or infarction, abnormalities of autonomic regulation, increased sympathetic tone¹¹, pericardial inflammation and by iatrogenic factors such as positive inotropic agents. One must also consider the reverse relationship between AF and AMI: AF with rapid ventricular response could also lead to a Type II MI. In this case, invasive therapy may not be warranted¹².

Typically, recent onset AF is well-tolerated and no specific treatment is required, except anticoagulation. Episodes are often repetitive and may last from minutes to hours². However, when it leads to hemodynamic instability, urgent treatment is needed to ensure rate control or return to sinus rhythm¹. When the fast ventricular rate results in haemodynamic collapse, direct current cardioversion is generally required.

Parenteral anticoagulation is recommended in addition to antiplatelet therapy in all AMI patients undergoing PCI¹. AF may be only a transient arrhythmia accompanying an acute MI, in an anticoagulant-naive patient. Consequently, in the periprocedural setting, parenteral anticoagulation is indicated. Routine of unfractionated heparin (UFH)is recommended¹. As an alternative to UFH, routine use of enoxaparin i.v. should be considered¹.

If an acute rhythm control strategy is pursued, amiodarone is the only pharmacological option¹. Intravenous amiodarone could facilitate electrical cardioversion and/or decrease the risk for early recurrence of AF after electrical cardioversion¹. Amiodarone may also be considered for rate control, if this strategy is chosen^1,11, with an initial dose of 5 mg/kg in 1 h followed by 50 mg/h¹².

Intravenous beta-blockers, including esmolol, propranolol and metoprolol are indicated for rate control and to reduce myocardial oxygen demands, if no clinical signs of acute heart failure (AHF) or hypotension are present^13,14. In these cases, the negative inotropic effect of β-blockers may result in further compromise of pump function. In the setting of AMI without AHF, short-acting beta blockers are preferred to allow rapid adjustment of the dose, based on the patient’s blood pressure and heart rate response. Close to the time of discharge, longer-acting beta blockers may be preferred.

In selected patients, intravenous digitalis should be considered for rate control when concomitant AHF and hypotension are present¹⁵. Usual dosage is 0.25 mg each 2 h up to 1.5 mg¹². Digoxin is ineffective in converting recent onset AF to sinus rhythm¹⁶. However, data from the ARISTOTLE AF trial showed that digoxin was independently associated with higher mortality rate in patients with AF regardless of HF¹⁷. In these patients, the risk of death increased with higher serum digoxin concentrations¹⁷. Among patients whose digoxin levels were greater than 1.2 ng/ml, the death rate increased by 56%¹⁷.

Administration of nondihydropyridine calcium antagonists might be considered to slow a rapid ventricular response in patients with AMI and AF only in the absence of significant HF or hemodynamic instability¹¹.

Vernakalant, flecainide and propafenone should not be used for rhythm control in patients with AMI¹¹.

Patients with AF and moderate-to-severe thromboembolic risk (CHA₂DS₂-VASc score ≥2) should be adequately treated with oral anticoagulants (either vitamin K antagonists or novel oral anticoagulants) to reduce the risk of stroke or systemic embolism². Consequently, patients with AMI and AF require combined antithrombotic therapy which results in a significant bleeding risk. Concomitant risks of cerebrovascular and coronary ischemic events and bleeding need to be balanced when deciding the duration and the type of antithrombotic therapy¹¹. Generally, dual antithrombotic therapy with a novel oral anticoagulant (NOAC) and a P2Y12 inhibitor (preferably clopidogrel) is recommended for the first 12 months after percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS), since it results in less major bleeding than triple therapy¹⁸. NOACs and the recommended doses are show in Table 1.

However, in AF patients with AMI, at least a short course of triple therapy (e.g. ≤1 week) is desirable¹¹ and should be continued up to one month when the bleeding risks are low and ischemic concerns prevail¹. These recommendations are based on the results of four RCTs which compared dual therapy with a P2Y12 inhibitor (mostly clopidogrel) plus a NOAC—dabigatran 110 mg or 150 mg b.i.d. (REDUALPCI)²⁰, rivaroxaban 15 mg o.d. (PIONEER AF-PCI)²¹, apixaban 5 mg b.i.d. (AUGUSTUS)²² or edoxaban 60 mg o.d.(ENTRUST-AF PCI)²³—vs. triple therapy with a VKA in AF patients with a recent ACS or undergoing PCI. All trials have shown a significant reduction of major or clinically significant bleeding, comparable rates of ischemic stroke, AMI and stent thrombosis with dual (NOAC + P2Y12) vs. triple (VKA + P2Y12 + aspirin) therapy. Since patients with AMI who develop AF are usually frail, with severe cardiovascular diseases and multiple comorbidities, they frequently have a high risk for both thrombotic and bleeding events. Consequently, the duration of the triple antithrombotic therapy should always take into consideration the balance between these risks. Assessment of ischemic and bleeding risks should be done using validated risk predictors (e.g. CHA₂DS₂-VASc, ABC, and HAS-BLED) with a focus on modifiable risk factors²⁴.

For paroxysmal AF, long-term antiarrhythmic therapy is not indicated when moderate to severe left ventricular systolic dysfunction or HF are absent²⁵ associated with increased in-hospital and long-term mortality rates. This notion is based on data collected before thrombolysis and additional modem methods of treatment became widely available, and no information is available on the significance of PAF in the general population with AMI in the thrombolytic era. The aim of the present study was to define the incidence, associated clinical parameters, and short- and long-term prognostic significance of PAF in patients with AMI in the thrombolytic era. Methods and Results - A prospective, nationwide survey was conducted of 2866 consecutive patients admitted with AMI in all²⁵ coronary care units in Israel during January/February 1992, 1994, and 1996 (thrombolytic era [TE].

In patients with AMI complicated with LV dysfunction, angiotensin-converting enzyme inhibitors appears to reduce the incidence of AF^26,13.

Statin therapy, possibly owing to an antiinflammatory effect, has been associated with a reduction in paroxysmal AF in patients with ischemic heart disease. In a retrospective study of over 3300 patients presenting with AMI and in sinus rhythm, early statin therapy (prescription within 48 hours of hospitalization) was associated with a reduced risk of AF²⁷.

In patients at risk of gastrointestinal bleeding, concomitant use of proton-pump inhibitors is reasonable²⁸.

The mechanisms of arrhythmogenesis depend on the stage of evolution of an AMI. Acute ischemia results in harmful consequences on the myocardial metabolism causing anaerobic glycolysis leading to acidosis and accelerated potassium efflux from the myocytes³¹. This generates electrolyte imbalance and electrical instability, which facilitate VAs development in the early phase of AMI³¹. Myocardial reperfusion may also result in abrupt changes in ionic and electrical balance promoting life-threatening Vas^32,12. Acute phase arrhythmias arise in the first 30 to 60 minutes and are attributed to reentry and abnormal automaticity³³. Chronic phase VAs appear after more than 48 hours following an AMI and are usually re-entrant and scar mediated, owing to a large MI resulting in a severely depressed LV function and LV remodeling. Monomorphic ventricular tachycardia (VT) is generally scar-related and is the typical presentation in patients with older fibrotic infarct areas in the myocardium¹².

Management of VAs is dependent on whether the arrhythmia is sustained or non-sustained, and if it results in hemodynamic compromise or occurs in an otherwise stable patient. The timing of the VA relative to the AMI plays another important role in the therapeutical decision. AMI related VAs can occur in multiple instances: pre-reperfusion VAs, reperfusion-induced VAs, early post-reperfusion VAs (within 48 h), late post-reperfusion VAs (>48 h after reperfusion), post-discharge arrhythmias¹². Ventricular fibrillation (VF) is the most frequent mechanism of prehospital sudden cardiac death (SCD)¹² and warrants immediate DCC. The development of VF in patients with an AMI, if occurring within the first 48 h, is associated with an increase in early mortality, but little or no increase in long term mortality after hospital discharge^34,12. Recurrent VF and/or polymorphic VT may be an indicator of incomplete reperfusion or recurrence of acute ischemia (e.g. acute stent thrombosis)³⁵. Urgent coronary angiography should consequently be considered³⁶.

Generally, sustained VAs (monomorphic or polymorphic) which result in hemodynamic instability call for rapid treatment by DCC. Non-sustained, recurrent or well-tolerated VAs require correction of the underlying ischemic substrate, possible added triggers and should not be treated with anti-arrhythmic drugs before reperfusion.

If ongoing myocardial ischemia is suspected to be responsible for the VA, coronary angiography and prompt and complete revascularization is the mainstay of treatment^37,1. Correction of electrolyte imbalances (especially hypokalemia and hypomagnesemia) is recommended in patients with VT and/or VF1. Hypokalemia during an AMI is a risk factor for VF. In the GISSI-2 trial, the probability of VF among patients with a serum potassium <3.6 mEq/L was almost twice as high as among patients with a higher serum potassium³⁸. Statin therapy has been showed to lower the incidence of premature ventricular complexes (PVCs) and non-sustained VT in patients with ACS³⁹. Drugs that inhibit the renin-angiotensin-aldosterone system, namely angiotensin converting enzyme (ACE) inhibitors also reduce the incidence of VAs in AMI⁴⁰. For the temporary management of malignant VT/VF refractory to usual treatment, deep sedation (preferably with benzodiazepines) is a viable therapeutic option which provides a reduction of the sympathetic drive associated with post-MI Vas^41,42. For patients with AMI without VAs, prophylactic antiarrhythmic drug treatment, with the exception of beta-blockers is not indicated and may be harmful².

The use of antiarrhythmic drugs (AAD) for VAs in AMI has been questioned and is largely based on observational data. Controlled randomized trials on the use of AAD for VAs in AMI are lacking². Prophylactic treatment with AADs is not indicated (with the possible exception of beta-blockers⁴³) and may be harmful¹. Useful antiarrhythmics, their classification, mechanisms of action, indications, dosing and possible side-effects are shown in Table 2.

Beta-blockers are first-line therapy in the management of VA in patients with AMI³⁶. Intravenous beta-blocker treatment is indicated for patients with VAs, in the absence of contraindications¹. VAs in the early or acute stages of an MI are in part related to enhanced automaticity, resulting from elevated catecholamines and beta receptor stimulation. At cellular level, the favorable electrophysiological effects of beta-blockers include decreased automaticity, which reduces the predisposition for triggered VA, and reduced conduction velocity, which impacts on the stability of re-entrant circuits²⁹. Beta-blocker use in the first 24 hours after AMI was associated with reduced in-hospital mortality in patients with sustained VT/VF⁴⁴. In the CAPRICORN trial, Carvedilol was shown to have significant anti-arrhythmic effects after AMI, suppressing both atrial and ventricular arrhythmias in these patients⁴⁵. Furthermore, in patients with severe recurrent VAs such as VT/VF storm, an intravenous beta-blocker can be useful⁴⁶. The mortality reduction observed with beta-blockade in the first 24 hours after AMI suggested that patients with sustained VAs benefited from acute beta-blockade without an increase in worsening heart failure⁴⁴.

Intravenous amiodarone is recommended for treatment of recurrent polymorphic VT¹. Amiodarone has a wide spectrum of action that includes blockade of depolarizing sodium currents and potassium channels that generate repolarizing currents. This results in prolongation of the refractoriness of the His-Purkinje system and ventricular contractile fibers thus preventing micro reentry⁴⁷. Consequently, amiodarone may inhibit or terminate VAs by decreasing automaticity and re-entry³⁶. Amiodarone (150–300 mg i.v. bolus) should be considered to acutely suppress recurrent VT or VF³⁶. However, over the long term, amiodarone treatment may result in increased mortality at 6 months³⁰. This outcome is most likely explained by confounding factors (e.g. patients with worse prognosis received amiodarone)³⁰. It may also occur due to residual adverse effects from amiodarone, possibly by further reducing myocardial contractility in already severely depressed left ventricles^47,48. Intravenous amiodarone may cause phlebitis (it is advisable to use a large peripheral vein, avoid administration >24 h and use preferably volumetric pump) and arterial hypotension¹².

Lidocaine may be used to treat recurrent VT with haemodynamic deterioration despite repetitive electrical cardioversion, if beta-blockers, amiodarone and overdrive stimulation are not effective or applicable^1,2. An observational study by Piccini et al suggested that lidocaine might be preferred over amiodarone for the treatment of sustained VT/VF complicating acute MI³⁰. In the first hours after VAs complicating acute MI, both amiodarone and lidocaine are associated with better survival³⁰. On longer term, amiodarone use was associated with a higher risk of death at 30 days and 6 months, while lidocaine use did not result in benefit or harm³⁰.